British Journal of Ophthalmology, 1985, 69, 192-196

Granulomatous uveitis in neurological diseaseDAVID M BACHMAN, A RALPH ROSENTHAL, AND ADRIAN B BECKINGSALE

From the Division of Ophthalmology, Stanford University Medical Center; and theDepartment of Ophthalmology, Leicester University School of Medicine

SUMMARY Five women with granulomatous uveitis were diagnosed as having probable multiplesclerosis. Three of the women developed curious iris nodules that resolved with topical prednisoloneacetate treatment. The association of granulomatous type uveitis, with or without iris nodules,should alert the ophthalmologist to inquire about neurological symptoms attributable to multiplesclerosis.

The association bf multiple sclerosis and granuloma-tous uveitis was first observed by Wuseke. I However,more commonly pars planitis and/or periphlebitisretinae has been emphasised as a common finding inpatients with multiple sclerosis.2-'8 It is the purpose ofthis paper to report five patients with probablemultiple sclerosis who developed a pars planitis-likepicture in addition to curious iris nodules and granu-lomatous uveitis.

Case reports

CASE 1A 39-year-old Caucasian woman developeddecreased sensation on the right side of her face,transient diplopia, slurred speech, and clumsiness.The' cerebrospinal fluid protein was 36 mg/dl (0.36g/l) with a gammaglobulin concentration of 12.4mg/dl, =0 124 g/l (normal 8 8, SD 2.6 mg/l, =0 09±0*03 g/l), and 4 white blood cells/mm3. A tuberculinskin test and a test for HLA-B27 were negative.Serum calcium was 9-1 mg/dl, =2-3 mmol/l (normal8*7-10-2 mg/l, =2-2-2 5 mmol/l); serum B,2 was 440(normal 200-1000) pg/ml (ng/l). A pattern-reversalvisual evoked potential showed normal latencies of119 in the right eye, and 166 ms in the left eye. Abrain computerised tomographic scan showed twodefinite periventricular areas of contrast enhance-ment on the left side of the cerebral cortex and twomore similar questionable areas of contrast enhance-ment in the left temporal lobe and right occipitalhorn. These were thought to be most consistent withdemyelinating disease. The patient was diagnosed ashaving multiple sclerosis.

She stated she had noted floaters for five years, andher referring ophthalmologist had treated her forrecurrent iritis. Examination of the eyes showed hervision to be 20/40 (6/12) right eye and 20/40 (6/12) lefteye. Eye movements were full without evidence ofinternuclear ophthalmoplegia. Both eyes had 1+anterior chamber cell and flare and 2+ fine cells in theanterior vitreous. The right macula was oedematous.Both eyes had patchy retinal venous sheathing andinferior vitreous fluffball opacities. There was slighttemporal optic nerve pallor, but Goldmann fieldswere full. Six months later she developed large,lardaceous keratic precipitates and grey-brown,round nodules at the pupillary border of the left eye(Fig. 1). The nodules disappeared on treatment withtopical prednisolone acetate 1%, only to recur oncessation of topical steroids.

Correspondence to Dr A R Rosenthal, Division of Ophthalmology, Fig. 1 Iris nodules atpupillary margin inpatient withStanford University Medical Center, Startford, CA 94305, USA. probable multiple sclerosis.

192

on February 22, 2021 by guest. P

rotected by copyright.http://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.3.192 on 1 M

arch 1985. Dow

nloaded from

Granulomatous uveitis in neurological disease

CASE 2A 50-year-old Caucasian woman presented withrecurrent iritis. Her neurological problems began atage 18, when she had developed severe right sidedheadaches, exacerbated by combing her hair, andtransient numbness of the right hand and arm. At age28 she awoke one day with pain and blurred vision inthe right eye and diplopia on left gaze. She was notexamined by an ophthalmologist, but a neurologistfound a left central scotoma and inferotemporalscotoma. There was also mild weakness of the righthand and arm and a decrease in stereognosis. Nocerebrospinal fluid protein electrophoresis was donein 1953. A tuberculin skin test was negative. Chestx-ray and pneumoencephalography were normal. Acarotid arteriogram was interpreted as showingspasm of cerebral arteries. After the arteriogramshe suffered a right hemiparesis and aphasia thatresolved over 48 hours, leaving a residual right hemi-sensory deficit. She was diagnosed as having eithermultiple sclerosis or an unusual cerebral vasculitis.At age 31 she developed paraesthesias of the leftlower extremity and binaural hearing loss. At age 41she had a hernia of the intervertebral disc between L4and L5 and underwent laminectomy. At age 48 aright ptosis was noted. Her gait became somewhatbroad-based over the next two years.At age 50 she was referted for ophthalmological

examination. Her best corrected visual acuity was

RE 20/40-2 (6/12) and LE 20/25 (6/7.5). There was2+ ciliary flush, large lardaceous keratic precipitates,and 1+ anterior chamber cells in both eyes. Therewas a posterior synaechia in the right eye. The iris ofthe left eye had a raised brown nodule on the surfaceof the stroma at 7 00 o'clock. Numerous fluffballswere present in the inferior vitreous of both eyes, butno snowbanking was seen on the pars plana. AnHLA-B27 test was positive. However, a rheuma-tologist thought she probably did not have ankylosingspondylitis. A VDRL was negative. The erythrocytesedimentation rate was 12 mm/h and serum calciumwas 8-9 mg/dl (2.2 mmol/l). Her iritis resolved, andthe iris nodule disappeared on topical prednisolonedrops. Pseudoexfoliation of the left lens capsule was

noted one year later. Six years later she developedsheathing of peripheral retinal venules and bilateralmacular oedema.At age 57 a neurological examination showed

proximal leg weakness, normal upper extremitystrength, but mild adiadochokinesia of both hands.Deep tendon reflexes were diffusely brisk withbilateral unsustained ankle clonus. There was

decreased awareness to pin prick in the right arm andleg, decreased vibration sense in the right ankle, anddecreased position sense in all toes. No dysmetria ofthe arms was present, but this was not tested in the

legs because of the leg weakness. Serum angiotensinconverting enzyme was normal at 19 (normal 10-30)units/ml. Her neurologist thought the most likelydiagnosis was multiple sclerosis. Other possibilitiesincluded an obscure, chronic meningoencephalitissuch as Harada's disease, or garcoidosis, though thelatter was very unlikely in view of the normal chestx-ray, serum calcium, and normal angiotensin con-verting enzyme level.

CASE 3A 38-year-old Caucasian woman developed a severeheadache. One week later she awoke with an un-comfortable pressure sensation in the left orbitalarea. Later that same day she observed a horizontalblack line with a bright line at one end in her leftvisual field. Over several hours the vision in the lefteye became totally grey. An ophthalmological exam-ination several days later showed vision in the righteye to be 20/40 (6/12). With the left eye she could onlycount fingers at 1 foot (30 cm). There was a leftrelative afferent pupillary defect. Eye movementswere normal. The optic nerve and retina were normalin both eyes. The diagnosis of left retrobulbarneuritis was made, and she was treated withprednisone 60 mg orally for five days. The vision inthe left eye gradually improved but did not return toits previous level.

In the ensuing months she noticed difficulty incoordinating her hands, trouble with her balance andgait, and decreased hearing in the left ear. The pastmedical history showed emotional problems andheavy drinking, for which she had received psychiatriccare. Further, she had suffered a closed head injurywith loss of consciousness two years previously. Hersister had been diagnosed as having definite multiplesclerosis.Examination of the eyes six months after the initial

episode of decreased vision in the left eye showedbest corrected visual acuity of RE 20/20 (6/6) and LE20/100 (6/30). There was a mild left relative afferentpupillary defect. On colour vision testing in the righteye she missed plates one and four of the HRR(Hardy, Rand, Rittler) pseudoisochromatic platesbut arranged the Farnsworth D-15 and Nagelanomaloscope correctly. With the left eye she failedall these tests. The visual field in the right eye wasnormal. In the left visual field a small central scotomato the I-4e test object was present. Eye movementtesting showed non-smooth pursuit to the patient'sleft, decreased optokinetic nystagmus with the drumrotating to the patient's left, and poor suppression ofthe vestibulo-ocular reflex on rotation to her left.Several moderate-sized lardaceous keratic precipi-tates were present on the corneal endotheliumof both eyes. There was an occasional cell in the

193

on February 22, 2021 by guest. P

rotected by copyright.http://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.3.192 on 1 M

arch 1985. Dow

nloaded from

DavidM Bachman, A Ralph Rosenthal, andAdrian B Beckingsale

Fig. 2a Iris nodules atpupillary border in patient withmultiple sclerosis.

anterior chamber in both eyes. Numerous largenodules were present at the pupillary border of theleft eye (Fig. 2a). There were many fine, white cells inthe anterior vitreous of both eyes. The disc in theright eye was normal. The left disc was pale. Therewere irregularities of the calibre of peripheral retinalarterioles in the left eye. The iris nodules resolved ontopical prednisolone acetate drops.A neurological examination showed mild left-

sided limb dysmetria and bilaterally hypotonic deeptendon reflexes. Laboratory examination showed acerebrospinal fluid protein of 0*69 g/l, 60 white bloodcells/mm3 with 83% lymphocytes, and a cerebro-spinal fluid gammaglobulin of 10-2 mg/l (0-1 g/l)(normal 0-0-035 g/l). A chest x-ray was normal. Noconsistent responses were found with monocularstimulation on visual evoked potential testing. Vary-ing major peaks were present with both eyesstimulated. Auditory evoked and somatosensorypotentials were normal. Serum and cerebrospinalfluidVDRLwere non-reactive. An electroencephalo-gram was normal. Computerised tomography of thebrain and orbits was normal. Serum proteinimmunoelectrophoresis showed a raised IgM of 400(normal 36-266) mg/dl (4 (normal 0.36-2-7 g/l) andnormal levels of IgG and IgA. Antinuclear anti-bodies were less than 1:20 dilution, which is normal.A lupus erythematosus cell preparation wasnegative. Purified protein derivative (PPD) testingwas negative at 48 hours, but tests for trichophytonand mumps were positive. Serum angiotension con-verting enzyme level was 28 (normal 10-30) units/ml.The white blood cell count was slightly raised at10-5x109/l, with 5% eosinophils. The patient hadHLA-B7 but not HLA-B27. This patient was thoughtto have multiple sclerosis because of a left retro-bulbar neuritis, a left visual pursuit deficit (signifying

Fig. 2b Recurrent iris nodules in association withlardaceous keratitic precipitates in samepatient.

a left parietal lobe lesion), and a raised cerebrospinalfluid gammaglobulin.The patient did well on medication until one year

later, when she noted decreased vision and a vibratingsensation of the left eye. There was a fibrinous iritis ofthe left eye with several posterior synechiae andseveral pupillary iris nodules. Fine vitreous cells andlarge fluffballs were noted in the inferior vitreous ofboth eyes. In addition the right eye showed large irispupillary nodules and lardaceous keratic precipitates(Fig. 2b). Topical prednisolone acetate therapy wasstarted and the iris nodules disappeared. Intravenousfluorescein angiography was normal at that time buteight months later showed bilateral cystoid macularoedema.

CASE 4A 52-year-old black West Indian nun presented withdecreased vision in the left eye. Best corrected visualacuity was RE 20/30 (6/9) and LE light perception.Old pigmented keratic precipitates were present inthe right eye but no active uveitis. Virtually confluentlardaceous keratic precipitates covered the wholeposterior corneal surface of the left eye. Posteriorsynechiae were also noted in the left eye. There wasmild right optic nerve pallor. The left eye was treatedwith topical and subconjunctival steroids andmydriatics. Ten days later the right eye developedanterior chamber cells and flare, and topical treat-ment was started in the right eye. The keratic precipi-tates slowly resolved over several months. At thistime examination of the left optic fundus waspossible, showing a pale left optic nerve.

194

on February 22, 2021 by guest. P

rotected by copyright.http://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.3.192 on 1 M

arch 1985. Dow

nloaded from

Granulomatous uveitis in neurological disease

The patient has had several episodes of spasticparaparesis since age 46. She has also had episodes ofconjugate lateral gaze palsy, spastic weakness of theright arm, and mild cerebellar ataxia of the arms,more marked on the right. Visual evoked potentialsshowed a considerably increased latency of the lefteye. A neurologist had diagnosed her as havingmultiple sclerosis. The patient was HLA-B27negative. Serology tests for syphilis and an auto-antibody screen were negative. X-rays of the skull,chest, and lumbar spine were normal.

CASE 5A 51-year-old Caucasian woman was referred forophthalmological examination. Best corrected visualacuity was RE 20/40 (6/12) and LE 20/50 (6/15). Botheyes showed extensive lardaceous keratic precipitatesand multiple posterior synechiae. Both optic nerveswere pale. The patient was treated with topicalsteroids and atropine drops, with resolution of thekeratic precipitates over three weeks. Mild anteriorchamber inflammation persisted for nearly fourmonths.

This patient had developed transient left legweakness when she was 23. At age 30 she had anepisode of retrobulbar neuritis. At 31 she hadepisodes of urinary incontinence and sensorydisturbances of the hands. Later that same year shedeveloped cerebellar ataxia of the upper limbs andright leg, with mild spasticity of all four limbs. Thisresolved gradually but became aggravated threeyears later. At age 41 she developed further worsen-ing of her leg weakness. Laboratory studies showed a

negative HLA-B27 and negative serology for syphilisand autoantibody screens. Skull, chest, and lumbarspine x-rays were normal. visual evoked potentialsdone when she was 53 were normal. A neurologisthad diagnosed probable multiple sclerosis.

Discussion

The five reported patients with granulomatousuveitis had a form of clinical multiple sclerosis (Table

1). In all cases the diseases most often associated withgranulomatous uveitis (tuberculosis, sarcoidosis, andsyphilis) were excluded by appropriate testing. Allcases had bilateral uveitis, and cases 1, 2, and 3 hadpars planitis and striking iris nodules. In no case didthe uveitis appear to coincide with an exacerbation ofthe neurological condition.One could suppose that cases 1 to 5 may be afflicted

with a disease similar to multiple sclerosis but aetio-logically different from other forms of multiplesclerosis, where the uveal tract remains uninvolved.It is also possible that these patients have somecombination of HL-A antigens which predisposethem to develop both a uveitis and multiple sclerosis.However rare the coexistence of these two diseasesfurther studies of such patients may help to explain apossible aetiology of multiple sclerosis.Wuseke first noted the association of multiple

sclerosis and uveitis in three patients with peripheraluveitis and multiple sclerosis.' Since then numerousauthors have reported a similar finding.47-911415Several patients have had pars planitis,'4 '5 whileothers showed discrete foci of choroiditis.4" Manypatients have been described who have had sheathingof peripheral retinal veins, with or without parsplanitis.23610 12-18 The coexistence of these two in-flammatory diseases in the same patient inevitablyleads to speculation as to a common aetiology,especially since the plaques of multiple sclerosis havea natural preference for a perivenous distribution.That both retina and brain are neuroectodermallyderived lends support to this hypothesis.

Diseases of the central nervous system other thanmultiple sclerosis which may be associated withuveitis include syphilis, tuberculosis, sarcoidosis,Vogt-Koyanagi-Harada disease, Behcet's syndrome,and toxoplasmosis. We found no evidence for any ofthese in our patients.One of Wuseke's patients had iris nodules of the

type initially described by Koeppe'9 in patients withtuberculosis. These nodules are found at the innerpupillary margin (Fig. 1). They have also been notedin syphilitic iritis and herpes zoster iritis.20 Our case 2

Table 1 Patients with granulomatous uveitis and neurological disease

Case Age Sex Neurological diagnosis Eyefindings Comment

1 39 F Probable multiple sclerosis Granulomatous anterior uveitis, iris nodules, vitritis,retinal venous sheathing

2 50 F Probable multiple sclerosis Granulomatous anterior uveitis, iris nodules, vitritis, HLA-B27+pseudoexfoliation, cystoid macular oedema

3 38 F Multiple sclerosis Retrobulbar neuritis, granulomatous anterior uveitis, Sister with multiple sclerosisiris nodules, vitritis but no uveitis

4 52 F Probable multiple sclerosis Granulomatous anterior uveitis, retrobulbar neuritis,cystoid macular oedema

5 52 F Probable multiple sclerosis Granulomatous anterior uveitis

195

on February 22, 2021 by guest. P

rotected by copyright.http://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.3.192 on 1 M

arch 1985. Dow

nloaded from

DavidM Bachman, A Ralph Rosenthal, andAdrian B Beckingsale

had a nodule on the surface of the iris stroma of thetype Busacca2l noted in patients with tuberculouslymphadenitis. Since the time of Friedenwald andFriedenwald22 these types of iris nodules have beenconsidered to be a sign of granulomatous uveitis,as they have also been seen in sarcoidosis andsympathetic ophthalmia, two clearly granulomatousdiseases.23 It is intriguing to note that pars planitis asdescribed by Brockhurst et al.24 is not associated withiris nodules, though it may present with 'gelatinous'exudates in the anterior chamber angle. In additionlardaceous keratic precipitates are rarely seen in parsplanitis.

Our patients showed that pars planitis, traditionallyconsidered a non-granulomatous uveitis, can presentwith iris nodules and lardaceous keratic precipitates,two clinical signs of granulomatous disease.Admittedly the ultimate differentiation betweengranulomatous and non-granulomatous disease canbe made only histologically. However, in most casesthe clinical picture showed should show the dif-ferences between the two. Perhaps an alteredimmune system in the patient with multiple sclerosismay cause granulomatous findings to, appear in adisease that is normally non-granulomatous. Never-theless these patients show that the occurrence ofgranulomatous uveitis should alert the ophthalmolo-gist to the possibility of multiple sclerosis.

This work was in part supported by an unrestricted research grantfrom Research to Prevent Blindness.

References

I Wuscke W. Seltener Augcnverandcrrungcn bci multiplcrSkierose. Ber Dtsch Ophthalmol Ges 1953;58:338-9.

2 ter Braak JWG, van Herwaarden A. Ophthalmo-encephalo-myelitis. Klin Monatsbl Augenheilkd 1933;91:316-43.

3 Ruckcr CW. Shcathing of the retinal vcins in multipic scicrosis.Mayo Clin Proc 1944;19:176-8.

4 Bucalossi A. Sulla presenza ed il significato de Icsioni chorio-retinichc nclla scierosi a placchc. Atti Soc Ottal Ital 1947;36:1 13-20).

5 Haarr M. Periphiebitis rctinac in association with multipicsclerosis. A cta Psychiatr Scand 1953;28: 175-90.

6 Orban T. Beitrage zu den Augenhintergrundsverandcrungen bciSclerosis multiplex. Ophthalmologica 1955;30:387-96.

7 D'Ermo F. Su di una rare complicanza oculare della sclerosi aplacche. Boll Oculist 1956;35:436-44.

8 Garde A, Tommasi M, Pellet M. A propos d'une observationanatomo-clinique d'encephalomyelite dissemin6e associee a uneuv6ite. Rev Neurol (Paris) 1957;97:139-42.

9 Garcin R. A propos de quclques observations d'uvdonevrites eten particulier d'association d'uv6ite et de syndromes neuro-logiques du type de la scldrose en plaques. Laval Med 1958;26:522-54.

1t) Ardouin M, Feuvrier YM, Catros A, Urvoy M. La periphldbiteretinienne de la scldrose en plaques. Rev Otoneuroophtalmol1960;32:3-8.

11 Pacurariu I, Pacurariu L. Complicatii kerao-uveale in scleroza inplaci. Oftalmologia (Buc) 1960;4:39-42.

12 Tschabitscher H, Sluga-Gasse E, Schinko H. HyperergiseheErkrankungen am Auge in Rahmen von multipler Sklerose.Wien Med Wochenschr 1962;112:279-85.

13 Moller PM, Hammerberg PE. Retinal periphiebitis in multiplesclerosis. Acta Neurol Scand 1963;39(Suppl 4):263-7t).

14 Archambeau PL, Hollenhorst RW, Rucker CW. Posterioruveitis as a manifestation of multiple sclerosis. Mayo Clin Proc1965 ;40:544-5 1.

15 Breger BC, Leopold IH. The incidence of uveitis in multiplesclerosis. Am J Ophthalmol 1966;62:540)-5.

16 Morse P. Retinal venous sheathing and neovascularization indisseminated sclerosis. Ann Ophthalmol 1975;7:949-52.

17 Younge BR. Fluorescein angiography and retinal venous sheath-ing in multipie sclerosis. Can J Ophthalmol 1976;11:31-6.

18 Bamford CR, GanlcyIJP, Sibiey WA, Laguna JF. Uveitis, peri-venous sheathing and multiple sclerosis. Neurology (Minnteap)1978;28: 119-24.

19 Koeppe L. Klinische Beobachtungen mit der Nernstspaltlampeund dem Hornhautmikroskop. Albrecht von Graefes Arch KlinOphthalmol 1917;92:115.

20 Vogt A. Weitere Ergebnisse der Spaltlampenmikroskopie desvorderen Bulbusabschnittes. Albrecht von Graefes Arch KlinOphthalmol 1923;111:91

21 Busacca A. Anatomische und klinische Beobachtungen derPupillarsaumknotchen (Koeppschen Knotchen) bei Iridozyklitis.Klin MonatsblAugenheilkd 1932;88:14.

22 Friedenwald H, Friedenwald F. Globular masses on the pupillarymargin in acute circumscribed chorioretinitis: a clinical andpathological study. Arch Ophthalmol 1926;55:1 13.

23 Woods AC. Endogenous inflammations of the uveal tract.Baltimore: Williams and Wilkins, 1961.

24 Brockhurst RJ, Schepens CL, Okamura ID. Uveitis I. Gonio-scopy. Am J Ophthalmol 1956;42:545-50.

196

on February 22, 2021 by guest. P

rotected by copyright.http://bjo.bm

j.com/

Br J O

phthalmol: first published as 10.1136/bjo.69.3.192 on 1 M

arch 1985. Dow

nloaded from